The critical problem with new experiments in using genetically engineered insects to fight malaria and dengue.

In the Cayman Islands, genetically modified mosquitoes are on the prowl. The insects are all male, and they’ve been engineered so that all their offspring die before reaching adulthood. By having sex with local females, they could father a new generation that perishes prematurely, before it gets the chance to spread diseases like dengue fever.

These GM insects, engineered by Luke Alphey at the University of Oxford, are part of a growing number of initiatives designed to fight disease by pitting mosquitoes against mosquitoes. Alphey’s tactic of breeding mosquitoes that beget unfit larvae is just one approach. Some groups are trying to make the insects more resistant to the disease-causing parasites they carry. Others have loaded them with life-shortening bacteria that outcompete those parasites. While some scientists warn of the unintended consequences of releasing such insects into the wild, others acknowledge that we need innovative new strategies for tackling mosquito-borne diseases like malaria and dengue fever, which affect hundreds of millions of people every year. (Figures for mosquito-borne illness are notoriously unreliable, but the World Health Organization estimates that each year there are 247 million cases of malaria, causing 881,000 deaths, and 50 million instances of dengue.)

But all of these recent attempts to turn mosquitoes into malaria- and dengue-killing machines have something in common: The modified mosquitoes need to have lots of sex to spread their altered genes through the wild population. They must live long enough to become sexually active, and they have to compete successfully for mates with their wild peers. And that is a problem, because we still know surprisingly little about the behavior and ecology of mosquitoes, especially the males. How far do they travel? What separates the Casanovas from the sexual failures. What affects their odds of survival in the wild? How should you breed the growing mosquitoes to make them sexier? Big question marks hang over these seemingly straightforward questions.

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Heather Ferguson from the University of Glasgow studies mosquito ecology. She views the knowledge gap in this field as a significant obstacle that stands in the way of the GM-mosquito initiatives. History tells us how dismally such initiatives can fare if they are not constructed on solid ecological foundations. In the 1970s and 1980s, several groups tried to control the mosquito population by releasing sterile males that would engage females in fruitless sex. The vast majority of the experiments failed.

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Their poor performance is often blamed on the fact that the males were sterilized with damaging doses of radiation. But they had many other disadvantages. Lab-bred mosquitoes are frequently reared in large, dense groups, which produces smaller, less competitive individuals. The artificial lights of a lab could also entrain their body clocks to the wrong daily rhythms, driving them to search for mates at the wrong time of the day. And in several cases, the modified males ignored the wild mosquitoes and preferred to mate with their lab-reared kin instead. These problems went unnoticed in lab tests, where the modified mosquitoes were compared with unaltered ones that had been raised in the same conditions. They seemed to be perfectly competitive, but they proved to be feeble challengers to their wild peers.

Given that we ended up with puny, frail mosquitoes that looked for the wrong mates at the wrong times of the day, it is no wonder that most of these early experiments in modifying mosquitoes failed. Compare this example to the case of the citrus-eating medfly, a pest that scientists also tried to control by releasing sterile males in the early 2000s. Just like mosquitoes, mass-reared medflies initially lost out to their wild peers. But scientists realized they could improve the medflies’ reproductive chances by feeding them lots of protein, which gives them energy for mating hunts, or ginger root oil, which produces a female-attracting scent. These simple measures had a big impact on the programs, which have successfully controlled medfly outbreaks in North and South America.

The new generation of GM-mosquito researchers learned from the failed experiments of the ‘70s and ‘80s and is trying to assess the competitiveness of its modified insects in the wild. Alphey’s group found that the ones released in the Cayman Islands fathered about10 percent of the local eggs within a few weeks. They were about half as successful as wild mosquitoes, which sounds poor, but is actually better than a lot of other modified insects, including the successful sterile medflies. The team has suggested that it could compensate for the males’ shortcomings by simply releasing more of them.

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Even if that works, it would still be better to make the GM mosquitoes as competitive as possible from the outset. The longer these programs run, the greater the odds that female mosquitoes will simply evolve to avoid the GM males. Again, there is historical precedent. In the 1970s, Japan tried to control the melon fly by releasing large numbers of sterile males. These efforts continued for many years before the females gained the ability to recognise and avoid the interlopers. The message is clear: We cannot afford a guerrilla war with disease-carrying insects. We need shock-and-awe tactics that have a big impact in a short period of time. And to achieve that, we need to plug the gap in our knowledge of mosquito ecology.

Unfortunately, Ferguson says, “A lot of the knowledge gaps that hindered previous attempts still remain.” In a recent review, she noted, “We have made substantially more headway in understanding the reproductive biology of species with no direct public health or economic importance, such as Drosophila, fur seals and blue tits, than we have done for this vector that kills millions.”

This crucial ecological research on mosquitoes is trapped in a financial no-man’s land. Organizations that fund basic research into issues like how insects behave assume that biomedical agencies will foot the bill, while these agencies are more likely to prioritize research with more obvious and immediate clinical impact. But the necessary ecological studies would not be expensive. Ferguson estimates that it would take just $500,000 to fund 10 students in the field, an act that “could easily quadruple our knowledge of this area within a few years.”

For example, in 2008, her student Kija Mg’Habi worked in an isolated, malarious part of Tanzania and discovered that among Anopheles gambiae (a species that carries malaria), the medium-sized males get the most sex. You might expect the biggest males to outcompete their smaller rivals, but they were actually six times less successful. This is exactly the type of information you need if you want your modified mosquitoes to outcompete their natural brethren.

Now, several scientists are trying to learn more about mosquitoes by setting up “semi-field studies.” These large outdoor spaces, enclosed by nets, are like mosquito aviaries. They should allow scientists like Ferguson to study large numbers of mosquitoes, both normal and modified, under natural but controllable conditions. These studies will not only be useful as testing grounds for GM strains; they should also start to provide some long-missing information about our mosquito adversaries. It may not be as sexy as modifying genes, but ecology is tantamount to knowing your enemy, and that surely is a cornerstone of victory.